Journal of Neurology

, Volume 263, Issue 4, pp 730–734 | Cite as

The role of mutations in COL6A3 in isolated dystonia

  • Katja Lohmann
  • Felix Schlicht
  • Marina Svetel
  • Frauke Hinrichs
  • Simone Zittel
  • Julia Graf
  • Thora Lohnau
  • Alexander Schmidt
  • Pablo Mir
  • Patricia Krause
  • Antony E. Lang
  • Hans-Christian Jabusch
  • Alexander Wolters
  • Christoph Kamm
  • Kirsten E. Zeuner
  • Eckart Altenmüller
  • Sadaf Naz
  • Sun Ju Chung
  • Vladimir S. Kostic
  • Alexander Münchau
  • Andrea A. Kühn
  • Norbert Brüggemann
  • Christine Klein
Original Communication

Abstract

Specific mutations in COL6A3 have recently been reported as the cause of isolated recessive dystonia, which is a rare movement disorder. In all patients, at least one mutation was located in Exons 41 and 42. In an attempt to replicate these findings, we assessed by direct sequencing the frequency of rare variants in Exons 41 and 42 of COL6A3 in 955 patients with isolated or combined dystonia or with another movement disorder with dystonic features. We identified nine heterozygous carriers of rare variants including five different missense mutations and an extremely rare synonymous variant. In these nine patients, we sequenced the remaining 41 coding exons of COL6A3 to test for a second mutation in the compound heterozygous state. In only one of them, a second rare variant was identified (Thr732Met + Pro3082Arg). Of note, this patient had been diagnosed with Parkinson´s disease (with dystonic posturing) due to homozygous PINK1 mutations. The COL6A3 mutations clearly did not segregate with the disease in the four affected siblings of this family. Further, there was no indication for a disease-modifying effect of the COL6A3 mutations since disease severity or age at onset did not correlate with the number of COL6A3 mutated alleles in this family. In conjunction with the relatively high frequency of homozygous carriers of reported mutations in publically available databases, our data call a causal role for variants in COL6A3 in isolated dystonia into question.

Keywords

Dystonia COL6A3 Exome sequencing Validation 

Notes

Acknowledgments

We are grateful to all participants in this study.

Compliance with ethical standards

Funding

This study was supported by funding from the German Research Foundation (LO1555/8-1 to K.L.). S.Z. is supported by an intramural grant of the University of Luebeck (E36-2014). She received honoraria for lectures from St. Jude Medical. A.A.K. and P.K. are supported by the German Research Foundation (KFO247). H.-C.J. has received funding from the Dystonia Coalition (NS065701; The Dystonia Coalition is part of the NIH Rare Diseases Clinical Research Network and has support from the NIH Office of Rare Diseases Research and National Institute of Neurological Disorders and Stroke). S.J.C. is supported by a grant of the Korea Healthcare Technology R & D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2206). A.M. is supported by the Possehl Foundation (Lübeck, Germany) and the Dystonia Coalition (USA). C.K. is a recipient of a career development award from the Herman and Lilly Schilling Foundation.

Conflict of interest statement

None of the authors declares any conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Katja Lohmann
    • 1
  • Felix Schlicht
    • 1
  • Marina Svetel
    • 2
  • Frauke Hinrichs
    • 1
  • Simone Zittel
    • 1
    • 3
  • Julia Graf
    • 1
    • 4
  • Thora Lohnau
    • 1
  • Alexander Schmidt
    • 1
    • 5
    • 6
  • Pablo Mir
    • 7
  • Patricia Krause
    • 8
  • Antony E. Lang
    • 9
  • Hans-Christian Jabusch
    • 10
    • 11
  • Alexander Wolters
    • 12
  • Christoph Kamm
    • 12
  • Kirsten E. Zeuner
    • 13
  • Eckart Altenmüller
    • 10
  • Sadaf Naz
    • 14
  • Sun Ju Chung
    • 15
  • Vladimir S. Kostic
    • 2
  • Alexander Münchau
    • 1
    • 3
  • Andrea A. Kühn
    • 8
  • Norbert Brüggemann
    • 1
    • 4
  • Christine Klein
    • 1
  1. 1.Institute of NeurogeneticsUniversity of Lübeck; Ratzeburger Allee 160LübeckGermany
  2. 2.Department of NeurologyBelgrade UniversityBelgradeSerbia
  3. 3.Department for Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of NeurogeneticsUniversity of LübeckLübeckGermany
  4. 4.Department of NeurologyUniversity of LübeckLübeckGermany
  5. 5.Kurt Singer Institute for Music Physiology and Musicians’ HealthHanns Eisler School of Music BerlinBerlinGermany
  6. 6.Interdisciplinary Competence Center Musicians’ Medicine, CharitéUniversity Medicine BerlinBerlinGermany
  7. 7.Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de SevillaHospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, CIBERNEDSevilleSpain
  8. 8.Department of Neurology, CharitéUniversity Medicine BerlinBerlinGermany
  9. 9.Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s DiseaseToronto Western HospitalTorontoCanada
  10. 10.Institute of Music Physiology and Musicians’ MedicineHanover University of Music, Drama and MediaHanoverGermany
  11. 11.Institute of Musicians´ MedicineUniversity of MusicDresdenGermany
  12. 12.Department of NeurologyUniversity of RostockRostockGermany
  13. 13.Department of NeurologyChristian Albrechts UniversityKielGermany
  14. 14.School of Biological SciencesUniversity of the PunjabLahorePakistan
  15. 15.Department of NeurologyAsan Medical Center, University of Ulsan College of MedicineSeoulKorea

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